title: Human erythropoietin gene delivery for cardiac remodeling of myocardial infarction in rats.
abstract: Considerable efforts have been made to exploit cardioprotective drugs and gene delivery systems for myocardial infarction (MI). The promising cardioprotective effects of recombinant human erythropoietin (rHuEPO) protein in animal experiments have not been consistently reproduced in clinical human trials of acute MI; however, the mechanisms underlying the inconsistent discrepancies are not yet fully understood. We hypothesized that the plasmid human erythropoietin gene (phEPO) delivered by our bioreducible polymer might produce cardioprotective effects on post-infarct cardiac remodeling. We demonstrated that intramyocardial delivery of phEPO by an arginine-grafted poly(disulfide amine) (ABP) polymer in infarcted rats preserves cardiac geometry and systolic function. The reduced infarct size of phEPO/ABP delivery was followed by decrease in fibrosis, protection from cardiomyocyte loss, and down-regulation of apoptotic activity. In addition, the increased angiogenesis and decreased myofibroblast density in the border zone of the infarct support the beneficial effects of phEPO/ABP administration. Furthermore, phEPO/ABP delivery induced prominent suppression on Ang II and TGF-β activity in all subdivisions of cardiac tissues except for the central zone of infarct. These results of phEPO gene therapy delivered by a bioreducible ABP polymer provide insight into the lack of phEPO gene therapy translation in the treatment of acute MI to human trials.
authors.affiliation: Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA. mdysgrace.lee@utah.edu
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Lee
authors.forename: Arlo N
authors.initials: AN
authors.lastname: McGinn
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Olsen
authors.forename: Kihoon
authors.initials: K
authors.lastname: Nam
authors.forename: Minhyung
authors.initials: M
authors.lastname: Lee
authors.forename: Sug Kyun
authors.initials: SK
authors.lastname: Shin
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D001120:Arginine / Q000008:administration & dosage* / Q000737:chemistry; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000737:chemistry; D004921:Erythropoietin / Q000737:chemistry / Q000235:genetics*; D018014:Gene Transfer Techniques; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011073:Polyamines / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling
chemical_list: D002316:Cardiotonic Agents; C554270:EPO protein, human; D011073:Polyamines; C534803:arginine-grafted bioreducible poly(disulfide amine)polymer; D004921:Erythropoietin; D001120:Arginine
keywords: Angiotensin; Gene delivery; Myocardial infarction; Remodeling